Biglycan Deficiency Causes Spontaneous Aortic Dissection and Rupture in Mice

Abstract

Background— For the majority of cases, the cause of spontaneous aortic dissection and rupture is unknown. An inherited risk is associated with Marfan syndrome, Ehlers-Danlos syndrome type IV, and loci mapped to diverse autosomal chromosomes. Analysis of pedigrees however has indicated that it may be also inherited as an X-linked trait. The biglycan gene, found on chromosome X in humans and mice, encodes a small leucine-rich proteoglycan involved in the integrity of the extracellular matrix. A vascular phenotype has never been described in mice deficient in the gene for small leucine-rich proteoglycans. In the breeding of BALB/cA mice homozygous for a null mutation of the biglycan gene, we observed that 50% of biglycan-deficient male mice died suddenly within the first 3 months of life. Methods and Results— Necropsies revealed a major hemorrhage in the thoracic or abdominal cavity, and histology showed aortic rupture that involved an intimal and medial tear as well as dissection between the media and adventitia. By transmission electron microscopy and biomechanical testing, the aortas of biglycan-deficient mice showed structural abnormalities of collagen fibrils and reduced tensile strength. Similar collagen fibril changes were observed in male as well as in female biglycan-deficient mice, which implies a role of additional determinants such as gender-related response to stress in the development of this vascular catastrophe only in male mice. Conclusions— The spontaneous death of biglycan-deficient male mice from aortic rupture implicates biglycan as essential for the structural and functional integrity of the aortic wall and suggests a potential role of biglycan gene defects in the pathogenesis of aortic dissection and rupture in humans.

Pathogenesis of Aortic Dissection: Elastic Fiber Abnormalities and Aortic Medial Weakness

“…25) Since fibrillin-1 is required for the assembly of microfibrils around elastin, their findings suggest that microfibril abnormalities are involved in elastic fiber fragmentation. In addition, aortic dissection was also reported to occur in biglycan-deficient mice 26) ; however, unlike human aortic dissection, the aortic dissection in this model occurred between the media and adventitia, and no histological changes were observed in elastic fibers. However, since biglycan is believed to be involved in elastogenesis and elastic fiber stabilization, the possibility cannot be excluded that ultrastructural abnormalities of elastic fibers were produced, leading to the development of aortic dissection.…”

Retrovirally Mediated Overexpression of Glycosaminoglycan-Deficient Biglycan in Arterial Smooth Muscle Cells Induces Tropoelastin Synthesis and Elastic Fiber Formation in Vitro and in Neointimae after Vascular Injury

“…8 Targeted disruption of biglycan leads to abnormal collagen fibrils and an osteoporosis-like phenotype 38 and recent studies show that this deletion leads to aortic dissection and rupture with altered collagen phenotypes and a suggestion of reduced collagen amounts. 9 These studies collectively point to a role for biglycan in regulating collagen accumulation. The mechanism by which this occurs, however, awaits further study.…”

“…7 In abdominal aortic aneurysms, where elastin is disrupted and fragmented, biglycan gene expression is decreased. 8 In addition, recent studies show that biglycan deficiency coincides with spontaneous aortic dissection and rupture in mice, 9 indicating a key role for this proteoglycan in vascular wall structure. On the other hand, biglycan stimulates proliferation and migration, 10 and induces cell elongation, features associated with a non-elastogenic phenotype.…”

Proteome Analysis of Human Arterial Tissue Discloses Associations Between the Vascular Content of Small Leucine-Rich Repeat Proteoglycans and Pulse Wave Velocity

“…8 Mice knockout models for SLRPs display disorganized collagen fibril network and loses functions of the connective tissue and present with different disorders related to abnormal collagen fibril sizes and network, such as aortic dissection and rupture, skin fragility, joint laxity, and tendon weakness. 9,10 In this study, we hypothesized that patients with a high degree of arterial stiffness display a specific protein expression pattern different from patients with a normal low degree of arterial stiffness. We applied a quantitative proteomic approach to identify differentially expressed proteins in individual arterial tissue samples obtained from patients with high and low PWV.…”